E-2006 (Lemborexant) was developed by Eisai and clinically used to treat insomnia. Studies have shown that the orexin system is a key regulator of the sleep-wake cycle, and thus orexin receptor antagonists have the potential to counteract inappropriate nighttime wakefulness and promote a regular sleep-wake cycle. E-2006 is an orexin receptor antagonist. In clinical trials, E-2006 can significantly improve sleep efficiency in patients with insomnia, including falling asleep fast and shorter time spent awake at night. In addition, E-2006 also shows great potential in the treatment of Alzheimer's patients with Irregular Sleep-Wake Rhythm Disorder (ISWRD). ISWRD is different from common insomnia, and has unmet clinical needs.
The chemical name of E-2006 is (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (hereinafter referred to as “Compound (I)”), and the structure is shown as follows:

Currently, no crystalline forms of compound (I) was disclosed. CN103153963B disclosed the structure of compound (I) and the process for preparing compound (I). The inventors of the present disclosure have repeated the preparation method in CN103153963B and amorphous solid was obtained. Compared with the crystalline form of the present disclosure, the amorphous solid has lower stability, lower density and poorer flowability, which is not suitable for the preparation of drug product. In addition, amorphous is the thermodynamically most unstable solid form, which is prone to crystal transformation or chemical degradation, resulting in a decrease in the purity of the compound. The preparation of amorphous is usually a rapid precipitation process to produce kinetically stable solid, which easily leads to excessive residual solvent. The particle property control in the preparation process is difficult.
The inventors of the present disclosure discovered excellent crystalline form CS2 of compound (I), which has advantages in at least one aspect of stability, melting point, solubility, in vitro and in vivo dissolution, hygroscopicity, bioavailability, adhesiveness, compressibility, flowability, processability, purification ability, formulation production, etc. Particularly, crystalline form CS2 has good stability, low hygroscopicity, good formulation processability, high in vitro dissolution and dissolution rate, which provides a new and better choice for the development of drug containing compound (I) and is of great significance.